Hyper IgM syndrome is a congenital immunodeficiency that is due to a predominant primary defect of antibody production. Hyper IgM syndrome is genetically heterogeneous. It may be due to 2 genetic mutations on the X chromosome, the CD40 ligand and NEMOgenes or due to 2 genetic mutations on autosomal chromosomes.

X-linked Hyper IgM due to mutation in the CD40 ligand gene is seen in boys and is clinically similar to X-linked agammaglobulinemia. Patients have small tonsils, often no palpable lymphnodes and become symptomatic during the 1st or 2nd year of life with recurrent pyogenic infections. These patients have marked susceptibility to P.carinii pneumonia and are often profoundly neutropenic. There is increased incidence of extensive verruca vulgaris, cryptosporidium enteritis, subsequent liver disease and increased risk of malignancy. Patients have very low serum concentrations of IgG and IgA with normal or elevated concentration of polyclonal IgM. They have normal number of circulating B & T cells. It has a poor prognosis.

X-linked Hyper-IgM due to mutations in NEMOgene is clinically characterized by anhidrotic ectodermal dysplasia. It leads to X-linked dominant incontinentia of pigmenti in females and is lethal in males.

Patients with autosomal Hyper IgM due to ALD mutation present much later in life and do not have susceptibility to P.carinii pneumonia. They have very low concentration of serum IgG, IgA and IgE and markedly elevated IgM. This condition is more benign as compared to boys with CD40 ligand defect.

Patients with autosomal recessive Hyper IgM due to mutations in CD40 are clinically indistinguishable from those with X-linked CD40 ligand defect.

Treatment consists of monthly infusion of IVIg and management of infections with antibiotics. For X-linked CD40 ligand defect early bone marrow transplant is the treatment of choice and prophylaxis for PCP is recommended.